Clinical and echocardiographic findings in patients with COVID-19 across different severity levels

Cardiovascular pathology can complicate the course of COVID-19. The study aimed to identify echocardiographic abnormalities and key prognostic factors influencing severe and fatal COVID-19 outcomes. This retrospective cohort study included clinical and echocardiogram data from 194 medical records of hospitalized patients with COVID-19: 100 moderate cases, 34 severe cases with favorable outcomes, and 60 severe cases with fatal outcomes. Severe patients with favorable outcomes had greater reductions in left ventricular systolic fraction of left ventricle compared to moderate cases (23.5% vs. 7.0%, respectively, p=0.008) and ejection fraction of left ventricle (14.7% vs. 3.0%, respectively, p=0.013), grade I diastolic dysfunction of the left ventricle (20.6% vs. 8.0%, respectively, p=0.044), and pulmonary hypertension (29.41% vs. 10.0%, respectively, p=0.006). Patients with fatal outcomes had a mean age of 67.1±1.51 years, chronic heart failure functional class II (58.3%), hypertension (50.0%), type 2 diabetes (43.3%), and obesity (33.3%). Compared to severe cases but with favorable outcomes, fatal cases had a greater decrease in left ventricular ejection fraction (36.7% vs. 14.7%, respectively, p=0.024), various types of myocardial dysfunction (51.7% vs. 29.4%, respectively, p=0.037) and a trend towards increased pulmonary hypertension (48.3% vs. 29.4%, respectively, p=0.074). Consequently, chronic heart failure class II, reduced left ventricular ejection fraction, various myocardial dysfunctions, and pulmonary hypertension emerged as key cardiac risk factors for severe disease progression and mortality in patients with COVID-19.


INTRODUCTION
To date, many diseases and pathological conditions have been identified as predictors of severe COVID-19, such as hypertension, coronary heart disease, diabetes, obesity, and age after 60 years [1,2].In-hospital mortality rates are higher when COVID-19 is associated with acute kidney injury, chronic heart failure (CHF), and cardiogenic shock [3].In patients with COVID-19 with severe acute respiratory syndrome, signs of myocardial damage are often observed (63.2%), which are manifested by changes in the ST segment and an increase in the level of troponin.In addition, transthoracic echocardiography reveals a wide range of cardiac abnormalities: global left ventricular (LV) dysfunction, LV diastolic dysfunction II and III grades, local LV wall dyskinesia, right ventricular (RV) dysfunction, and pericardial exudation.Patients with COVID-19 may have the highest mortality risk (31.7%) in the presence of echocardiographic abnormalities and myocardial involvement [4].A history of heart failure (HF) in patients with COVID-19 is associated with a higher mortality rate than in pa-tients hospitalized for acute HF without COVID-19 [5,6].Therefore, this syndrome can be an independent predictor of nosocomial mortality from COVID-19 [7].
The severe form of COVID-19 is closely related to RV dysfunction.Meta-regression studies have shown that RV dysfunction is observed in 20% of patients with COVID-19.It is also a risk factor for all-cause death [8,9].Echocardiographic studies revealed RV dilation with or without systolic dysfunction in 62% of patients with COVID-19.RV dysfunction is increased RV afterload caused by pulmonary thrombosis or embolism [10].RV enlargement (41%) and RV dysfunction (27%) were also associated with elevated D-dimer and C-reactive protein levels.At the same time, LV function was hyperdynamic or normal in 89% of patients [11,12].
SARS-CoV-2 virus can induce a range of complications, including thrombotic microangiopathy, venous thromboembolism, endothelial dysfunction, and impaired pulmonary hemodynamics, which can lead to increased pressure in the pulmonary artery.Echocardiographic evaluations in hospitalized patients with COVID-19 reveal the presence of PH in approximately 12-13% of cases.In addition, coronavirus disease exacerbates concomitant PH that is accompanied by chronic congestive heart failure or chronic obstructive pulmonary disease.PH, in turn, worsens the course of the disease and increases the risk of complications [13].
Histological studies have established that the walls of pulmonary vessels were thickened in patients who died from COVID-19, which was not observed in those who died from the severe acute respiratory syndrome (SARS) in 2002-2004 or from the H1N1 flu (2009)(2010).Such vascular changes are important for the formation of PH [14].
Echocardiography is useful for detecting the accumulation of pericardial effusion and cardiac tamponade, as it was described in the case of a 47-year-old woman with COVID-19 [15].There is evidence that COVID-19 increases the risk of acute myocardial infarction or ischemic stroke by destabilizing atherosclerotic plaque in blood vessels [16].In critically ill patients with myocarditis, myopericarditis, stress cardiomyopathy, or myocardial infarction, a cardiogenic shock could develop occasionally [17].A fatal case of a severe course of COVID-19 in a 63-year-old man complicated by fulminant myocarditis with a sharp decrease in LV systolic function and cardiogenic shock was described.In this patient, the echocardiography showed decreased left ventricular ejection fraction associated with elevated troponin (11.37 g/L) and a very high level of IL-6 (272.40 pg/mL) [18].In many cases of COVID-19 (36.54%), echocardiography results led to therapeutic changes [19].
Thus, numerous studies indicate the importance of echocardiography in managing hospitalized patients, enabling the diagnosis of concurrent cardiac pathologies and informing necessary adjustments in treatment strategies [20].However, a persistent challenge is differentiating between preexisting cardiac anomalies and those induced by COVID-19 infection [21].This study aimed to establish echocardiogram abnormalities and identify the most important prognostic factors associated with severe and fatal COVID-19 outcomes.

Study design and participants
This retrospective cohort study is part of a larger project conducted by Ivano-Frankivsk National Medical University, titled "The course of infectious diseases against the background of concomitant pathology, combined chronic infections and invasions, correction of treatment" (state registration number: 0119U100571, implementation dates: 2021 -2023).We analyzed echocardiographic data from 194 patient records at the Regional Clinical Infectious Diseases Hospital of Ivano-Frankivsk, Ukraine.The study included 100 cases of moderate severity, 34 severe cases without fatalities (with respiratory failure (RF) grades I to III), and 60 cases of severe RF (grades III to IV) that resulted in death.The inclusion criteria for each group of patients were the corresponding severity and outcomes of the disease.Exclusion criteria were lung cancer and death not caused by respiratory failure.

Clinical assessment
Patient diagnoses, including respiratory failure (RF), concomitant pathologies, echocardiographic data, and body mass index (BMI) were extracted from medical records.Echocardiograms were performed using a Toshiba Nemio XG machine, employing apical and parasternal long-axis B-and M-mode imaging with a 3.5 MHz sector transducer.The protocol adhered to the joint guidelines of the American Society of Echocardiography and the European Association of Cardiovascular Imaging [22].CHF was diagnosed according to the New York Heart Association 1994 criteria.Pulmonary hypertension was determined by the peak tricuspid regurgitation velocity according to the 2022 ESC/ERS guidelines [23], with velocities ≤2.8 m/s rated as low (degree 1), between 2.9 and 3.4 m/s as intermediate (degree 2), and >3.4 m/s as high (degree 3).BMI was calculated to categorize obesity: class I for BMI between 30 to 35, class II for BMI between 35 to 40, and class III for BMI over 40, following Center for Disease Control and Prevention (CDC) guidelines.Hypertension stages I, II, and III were determined per the ESC/ESH guidelines for managing arterial hypertension [24].
The severity of COVID-19 was assessed following the World Health Organization clinical management guidance for COVID-19 [25].The classification of Adult Acute Respiratory Distress Syndrome was based on the widely recognized 2012 Berlin Definition [26].

Statistical analysis
We used Pearson's chi-square test (χ2) to compare the frequency of presented pathologies in groups of patients and Student's t-test to compare the mean age of patients.For this reason, an online statistic calculator was used, and significant differences were considered when p<0.05 [27].
The severe group with favorable outcomes included 34 patients-19 men (55.9%) and 15 women (44.1%) -ranging in age from 44 to 81 years, with a mean age of 63.9±1.7 years.The average age of these patients did not statistically differ from those with moderate severity (60.78±1.38,t=1.215, p>0.05).Patients were hospitalized for 12-36 days (22.2±1.0 days on average).X-ray and ultrasound of the lungs showed bilateral pneumonia with damage of 50% -80% of the lung fields.Respiratory insufficiency was categorized as follows: Grade I in 14 patients (41.2%),Grade II in 13 patients (38.2%), and Grade III in 7 patients (20.6%).A comparison of comorbidities with the moderate Other inflammatory changes identified were a thickening of the pericardium in 16.0% of patients and a moderately increased amount of pericardial fluid in 8.0%.PH was detected in 10.0% of patients (first degree -7.0% and second degree -4.0%) (Table 2).It could arise or intensify against the background of lesions of pulmonary capillaries (microthrombi, vasculitis) and increased peripheral resistance to blood flow in the small circle of blood circulation [31,32].
Echocardiography in patients with severe COVID-19 revealed more frequent and pronounced cardiac abnormalities compared to those with moderate disease severity (Table 2).Thus, diffuse cardiosclerosis was significantly more common in severe cases (73.5%) compared to moderate cases (36.0%, p<0.001).Similarly, fibrosis and compaction of the AV were observed in 35.3% of severe cases versus 11.0% in moderate cases (p=0.001), and valve regurgitation was seen in 23.5% of severe cases, significantly higher than the 3.0% in moderate cases (p<0.001).The

Echocardiographic findings in patients with moderate and severe COVID-19 with a favorable outcome
In moderate patients, a number of abnormalities were revealed by the echocardiography: LV hypertrophy in 22.0%, diffuse cardiosclerosis in 36.0%,aortic aneurysm in 1.0%, stenosis of the aortic opening in 2.0% and AV insufficiency in 3.0%.Compaction and fibrosis were also observed in the aortic valve in 11.0% of cases, the mitral valve (MV) in 21.0%, and the tricuspid valve (TC).These pathologies are more likely preexisting conditions rather than directly associated with COVID-19.Blood flow regurgitation was also noted in the mitral valve (18.0%), aortic valve (3.0%), and tricuspid valve (11.0%).A significant reduction in LV ejection fraction was observed: 7.0% of patients showed a pronounced decrease to less than 28%, and 3.0% experienced a reduction to less than 50%.Grade I diastolic dysfunction of the LV was recorded in 8.0% of the cases (Table 2).These changes suggest decreased LV relaxation, likely due to preexisting conditions such as hypertrophy and cardiosclerosis.However, these issues may be exacerbated by the systemic immune inflammatory

Echocardiographic findings in patients with severe COVID-19 with fatal outcomes
Echocardiographic analysis revealed notable differences between patients with severe COVID-19 who had fatal outcomes and those with favorable outcomes.In patients with fatal outcomes, aortic arch expansion was observed in 11.7%, compared to none in the favorable outcome group (p=0.039).Additionally, compaction and fibrosis of the AV were more prevalent in fatal cases (58.3%) than in severe cases with favorable outcomes (35.3%, p=0.032).A significant decrease in ejection fraction was also more common in fatal cases (36.7% vs. 14.7%, p=0.024).Various types of myocardial dysfunction were observed, including grade I diastolic dysfunction of the LV (hypertrophic type) in 26.7% of fatal cases.Other dysfunctions like grade II diastolic dysfunction (pseudonormal type), LV hypokinesia, paradoxical movement of the LV, and dyskinesia of the interventricular septum were seen in isolated cases, but these did not show statistical differences between the two groups.The overall incidence of myocardial dysfunction was significantly higher in patients with a critically severe course and a fatal outcome (51.7% vs. 29.4%,respectively, p=0.037).There was a trend towards an increase in the frequency of pulmonary hypertension (48.3% versus 29.4%, respectively, p=0.074) (Table 4).

DISCUSSION
The study showed that the average age of hospitalized patients was 60 years or older, with the risk of a fatal outcome more pronounced at an average age of 67.1±1.51 years.Comorbidities such as obesity class II (BMI > 35.0-39.9),type 2 diabetes, hypertension, chronic heart pathology, and CHF were often found in patients with severe COVID-19.These underlying chronic diseases are generally recognized as risk factors for severe diseases.Echocardiographic examinations revealed a broad spectrum of cardiac abnormalities, indicating underlying myocardial pathologies.The most common underlying disease was diffuse cardiosclerosis, which presented in 73.5% of patients with a favorable outcome and 90.0% of patients with a fatal outcome.Further echocardiographic findings included aortocardiosclerosis features like aortic arch expansion, fibrosis, and thickening and regurgitation of the aortic mitral and tricuspid valves.Such data reflects age-related changes in the heart.Heart failure, a significant outcome of cardiosclerosis, was more frequently ob-MV also showed more fibrosis and compaction in severe cases (41.2%) compared to moderate cases (21.0%, p=0.021).There were changes in the dimensions of the walls and chambers of the ventricles: LV hypertrophy in 41.1% vs. 22.0%, respectively, p=0.030;RV dilatation in 23.5% vs. 7.0%, respectively, p=0.008;PA dilatation (2.1 -2.5 cm in diameter) in 35.3% vs. 18.0%, respectively, p=0.037.A violation of the contractile function of the LV was observed more often in severe patients than in moderate patients.Thus, Impairments in LV contractile function were more frequent in severe cases, with a decrease in systolic fraction observed in 23.5% (versus 7.0% in moderate cases, p=0.008), a decrease in ejection fraction in 14.7% (versus 3.0%, p=0.013), and grade I diastolic dysfunction of LV (hypertrophic type) in 20.6% (versus 8.0%, p=0.044).In severe patients, PH was more prevalent (29.4%) compared to moderate cases (10.0%, p=0.006), with a higher incidence of degree 2 PH in severe patients (14.7% vs. 4.0% in moderate cases, p=0.031).A compaction of pericardium with exudation was also found more often in patients with a severe course of COVID-19 (20.6 % vs. 8.0%, respectively, p=0.044) (Table 2).

Clinical characteristics and comorbidities of patients with severe COVID-19 with a fatal outcome
The group of patients with a severe course and fatal outcome consisted of 60 people (51.7% men and 48.3% women) aged 33-89 years (average age was 67.1±1.51 years).The average age was not statistically different from patients who survived severe COVID-19 (average age 63.9±1.7 years, t=1.407, p>0.05) but was significantly higher than those with moderate severity (average age 60.78±1.38 years, t=2.965, p<0.01).These patients were hospitalized for 1-46 days (average 14.47±1.51days) and commonly exhibited bilateral pneumonia, affecting 75%-90% of lung fields, along with III-degree respiratory failure.Medical records indicated several concurrent cardiovascular and metabolic diseases.In patients with a fatal outcome, diffuse cardiosclerosis (90.0% vs. 73.5%,p=0.03) and CHF (61.7% vs. 23.5%,p=0.0004), particularly functional class II CHF (41.7% vs. 14.7%, p=0.008), were more prevalent compared to those with a favorable outcome.The frequency of other conditions like hypertension, diabetes, obesity, and others was similar in both groups (Table 3).On the other hand, hypertension stage III was observed in only four patients who had a fatal outcome, and a post-stroke condition was noted in one patient.Such data indirectly indicate a more severe clinical course of hypertension (Table 3).Undoubtedly, HF was the most important aggravating factor and had a direct effect on increasing the frequency of adverse outcomes.Background chronic heart failure may worsen or can be a consequence of acute myocarditis under the influence of The echocardiographic confirmation of HF included a reduction in the LV ejection fraction, observed in 36.7% of patients with fatal outcomes and 14.7% of patients with favorable outcomes.There were cases of diastolic dysfunction of the LV grade I (prolongation of the interval of slow blood filling the LV), which occurred in 20.6% of severe patients with favorable outcomes and 26.7% in fatal cases.LV diastolic dysfunction grade I may also increase pressure in the left atrium and pulmonary vessels [33].
The increase in the frequency of PH was quite typical for patients with massive lung damage (70% -90%).In our study, PH was present in 48.3% of patients with fatal COVID-19 outcomes.While PH in moderate COVID-19 cases may be an underlying condition, its increased prevalence in severe cases, particularly those with fatal outcomes, is likely attributed to extensive lung damage [14,34].This increase in PH could be driven by mechanisms such as endothelial dysfunction [14,34], microangiothrombosis in alveolar capillaries [35], and a reduction in nitric oxide levels [36], all contributing to increased resistance in the pulmonary circulation.
The presence of PH further complicates pulmonary gas exchange due to shunting in the pulmonary capillaries [37] and adds to the hemodynamic burden on the right side of the heart.This was evidenced by the observed dilation of the right ventricle in 18.0% of fatal cases, the right atrium in 5.0%, and the pulmonary artery in 33.3%.These findings suggest a possible association between post-COVID pulmonary gas exchange disorders, cardiovascular complications, and the development of PH [38,39].
Endothelial dysfunction has a very important role in the progression of severe COVID-19, particularly observed in patients with type 2 diabetes mellitus [40] and hypertension [41].It has been established that endothelial dysfunction is a universal pathogenetic factor of multiorgan lesions in patients with COVID-19.In patients with HF, there is an increased expression of angiotensin-converting enzyme 2 receptors (ACE2), which could explain the exacerbated severity of COVID-19 in these individuals [42,43].The pericardial thickening without/with exudation in the pericardial sac is likely associated with a systemic inflammatory response and cytokine proinflammatory storm [44][45][46][47].
The study corroborated well-established risk factors for severe COVID-19, which include an average age over 60 years (in our study, the average age was 63.9±1.7 years), CHF, hypertension, type 2 diabetes mellitus, and obesity class II.These risk factors were consistent among participants with severe disease.Moreover, the most critical factors leading to fatal outcomes included an older average age of 67.1 years, CHF functional class II, reduced ejection and systolic fractions of the left ventricle, multiple LV dysfunctions, and pulmonary hypertension.
One of the strengths of the study is the analysis of echocardiography data and its correlation with the severity of the disease, patient outcomes, and age.One limitation is the absence of inclusion and exclusion criteria based on the different management protocols for COVID-19, which could influence patient outcomes.Additionally, the frequent use of echocardiography to monitor disease progression could reveal valuable insights into the dynamic nature of the illness.

CONCLUSION
The clinical and echocardiographic examinations conducted in this study identified critical cardiological risk factors that con-

Table 4 . Transthoracic echocardiography findings in patients with severe COVID-19 with favorable and fatal outcomes, N=94
tribute to the severe progression of COVID-19 and increase the likelihood of a fatal outcome.These include chronic heart failure (CHF FC II), reduced ejection and systolic fraction of the LV, and various dysfunctions of both the left and right ventricles.